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NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp) AND Brugada syndrome (shorter-than-normal QT interval)

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 12, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003317072.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)]

NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)

Gene:
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)
HGVS:
  • NC_000003.12:g.38630393G>A
  • NG_008934.1:g.24280C>T
  • NM_000335.5:c.310C>TMANE SELECT
  • NM_001099404.2:c.310C>T
  • NM_001099405.2:c.310C>T
  • NM_001160160.2:c.310C>T
  • NM_001160161.2:c.310C>T
  • NM_001354701.2:c.310C>T
  • NM_198056.3:c.310C>T
  • NP_000326.2:p.Arg104Trp
  • NP_001092874.1:p.Arg104Trp
  • NP_001092875.1:p.Arg104Trp
  • NP_001153632.1:p.Arg104Trp
  • NP_001153633.1:p.Arg104Trp
  • NP_001341630.1:p.Arg104Trp
  • NP_932173.1:p.Arg104Trp
  • NP_932173.1:p.Arg104Trp
  • LRG_289t1:c.310C>T
  • LRG_289:g.24280C>T
  • LRG_289p1:p.Arg104Trp
  • NC_000003.11:g.38671884G>A
  • NM_198056.2:c.310C>T
  • Q14524:p.Arg104Trp
Protein change:
R104W
Links:
UniProtKB: Q14524#VAR_074319; dbSNP: rs199473055
NCBI 1000 Genomes Browser:
rs199473055
Molecular consequence:
  • NM_000335.5:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Brugada syndrome (shorter-than-normal QT interval)
Identifiers:
MedGen: CN221547

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004020423Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jun 12, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]
PMID:
20129283
PMCID:
PMC2822446

Clinical presentation and follow-up of women affected by Brugada syndrome.

Berthome P, Tixier R, Briand J, Geoffroy O, Babuty D, Mansourati J, Jesel L, Dupuis JM, Bru P, Kyndt F, Guyomarch B, Thollet A, Behar N, Mabo P, Sacher F, Probst V, Gourraud JB.

Heart Rhythm. 2019 Feb;16(2):260-267. doi: 10.1016/j.hrthm.2018.08.032. Epub 2018 Sep 5.

PubMed [citation]
PMID:
30193851
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020423.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: SCN5A c.310C>T (p.Arg104Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249552 control chromosomes. c.310C>T has been reported in the literature in individuals affected with Brugada Syndrome (example, Kapplinger_2010, Clatot_2012, Berthome_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report reproducible experimental evidence evaluating an impact on protein function (example, Clatot_2012, Doisne_2021). The most pronounced variant effect results in abolished sodium current in-vitro and a dominant-negative effect on wild-type channel assembly that was reproducible in a murine model. The following publications have been ascertained in the context of this evaluation (PMID: 30193851, 22739120, 34122134, 20129283). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 16, 2024